T cells of the helper-inducer subset recognize antigen and the class II MHC molecules expressed on accessory cells. For globular protein antigens, the antigen must be processed by the accessory cells prior to T cell recognition. Small peptides can substitute for processed antigen since they can be recognized by T cells when prefixed accessory cells or Ia bearing planar membranes are used to present antigen. We have recently been able to demonstrate that immunogenic peptides bind specifically to Ia-molecules. With a panel of 12 such peptides we have found a correlation between the capacity of an Ia molecule to bind a particular peptide and the capacity of that Ia to serve as a restriction element of the same peptide. Furthermore, we have provided evidence that the complex formed between Ia and peptide is immunologically relevant and that it is this moiety that is recognized by the T cell receptor. We plan to extend our investigations of the role of antigen-Ia interactions in T helper cell responses as follows: 1) To investigate the structural characteristics of peptides that enable them to interact with Ia. 2) To identify the peptide regions within a naturally occurring protein antigen that bind to Ia and to correlate this binding activity to the immunogenicity of these same peptides. 3) To identify and characterize the region(s) within Ia molecules that form the antigen binding site(s) of Ia. 4) To demonstrate and characterize the tri-molecular complex between Ia, antigen, and T cell receptor. 5) To investigate the stoichiometry of Ia-peptide interaction in an attempt to understand why a small fraction of affinity purified Ia appears capable of binding peptide.